Identification of the molecular genetic basis of the hepatic veno-occlusive disease with immunodeficiency syndrome

骨髓移植最严重的并发症之一是静脉闭塞症(VOD)，又称窦性梗阻综合征(SOS)。这种情况发生在10%的移植患者中，其特征是肝功能异常、肝脏增大、凝血异常、液体滞留，最终导致多个器官衰竭，在30%-50%的病例中死亡。VOD的原因尚不清楚，也无法预测其在个别患者中的发生。已经描述了8个家庭，其中一些人死于一种在临床和组织上与VOD无法区分的疾病。受影响的个体也有某种形式的免疫缺陷(因此称为Vodi)，这些异常是以常染色体隐性遗传模式遗传的。所有八个人都来自黎巴嫩，这表明在所有远亲家庭中，单一的基因祖先突变是导致这种疾病的原因。我们已经获得了其中三个家庭的遗传物质，并正在确定致病基因异常的方法。我们假设，了解这种异常将导致对骨髓移植后发生的VOD的理解。我们使用了分散在基因组中的800个多态遗传标记来确定遗传异常的位置，并将缺陷定位到2号染色体的一个区域，该区域包含大约37个已知和预测的基因。我们现在的目标是确定候选区域中的哪个基因(S)对沃迪负有责任，并计划检查移植后患有VoD的个体的DNA，以确定他们是否有相关的异常。发现Vodi基因将通过携带者检测的可用性使这些家庭受益，并可能导致对骨髓移植后发生的静脉闭塞疾病的了解。

One of the most serious complications of bone marrow transplantation is veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS). This condition occurs in 10% of transplanted patients and is characterised by abnormalities of liver function, enlargement of the liver, clotting abnormalities, fluid retention and finally failure of multiple organs and death in 30-50% of cases. The cause of VOD is unknown, and its occurrence cannot be predicted in individual patients. Eight families have been described in whom a number of individuals have succumbed to a condition which is clinically and histologically indistinguishable from VOD. Affected individuals also have a form of immunodeficiency (hence termed VODI), and the abnormalities are inherited in an autosomal recessive pattern. All eight are of Lebanese origin, suggesting that a single genetic ancestral mutation was responsible for the disorder in all families, who are distantly related. We have access to genetic material from three of these families, and are on the way to identifying the causative genetic abnormality. We hypothesise that understanding this abnormality will lead to an understanding of VOD which occurs after bone marrow transplantation. We have used 800 polymorphic genetic markers scattered throughout the genome to identify the location of the genetic abnormality, and have localised the defect to a region of chromosome 2 which contains approximately 37 known and predicted genes. We now aim to determine which of the gene(s) in the candidate region is responsible for VODI, and plan to examine DNA from individuals who have had VOD after transplantation to determine if they have a related abnormality. Finding the VODI gene will benefit these families through the availability of carrier detection and may also lead to an understanding of the veno-occlusive disease that occurs after bone marrow transplantation.